Hematopoietic Clonal Expansion in Mpn by Hmga2

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by clonal proliferative hematopoiesis with increased blood cell count. Clonal expansion mechanisms in MPN and related disorders such as myelodysplastic syndromes (MDS) remain to be elucidated. Although mutations in the JAK2 gene lead to a proliferative hematopoiesis in majority of MPN and some MDS, the mutation alone does not cause a clonal expansion. In addition to JAK2 mutations, several genetic abnormalities, including TET2 and polycomb group genes involving epigenetic regulation have been reported in patients with MPN. Moreover, overexpression of HMGA2 due to removal of specific sites in its 3́ untranslated region for regulatory let-7 micro RNAs may contribute to the proliferative hematopoiesis with conferring a growth advantage at the level of a hematopoietic stem cell in some cases with MPN. description of this disease entity. Discovery of JAK2V617F provided the novel insight that the mutation causes constitutive activation of JAK-STAT signaling pathway, which leads to a proliferation of blood cells. However, it turned out that the JAK2V617F does not necessarily confer a clonal growth advantage. In fact, both JAK2V617F and JAK2V617F cells similarly have clonality in X-linked clonality assay and chromosomal analysis in blood cells from MPN patients. In addition, secondary AML following MPN often derive from JAK2V617F cells rather than JAK2V617F cells-. Furthermore, although JAK2V617F mutation is sufficient to cause MPN, JAK2V617F mutant cells failed to repopulate in bone marrow transplantations (BMT). Based on these findings, additional molecular pathogenesis other than JAK2V617F have been explored in MPN, bringing a variety of new insights, such as mutations and/or expression changes of genes involving cytokine signaling cascade, transcription, and epigenetic regulation-. In addition, overexpression of the high mobility group